Ubiquitination and ubiquitin-like modifications in metabolic dysfunction-associated steatotic liver disease: mechanisms and implications.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex metabolic disorder that encompasses a spectrum of conditions, from simple hepatic steatosis to metabolicassociated steatohepatitis (MASH). MASH is characterized by inflammation and accelerated fibrosis progression, which can ultimately lead to cirrhosis and hepatocellular carcinoma. Given its steadily increasing prevalence, MASLD has emerged as a global health epidemic. Significantly, MASLD represents a stage where liver function can still be partially restored through dietary interventions and physical exercise. However, the longterm sustainability of these lifestyle changes poses a significant challenge. Furthermore, the complex and heterogeneous nature of MASH complicates the development of pharmacotherapeutic strategies and the identification of reliable biomarkers for effective treatment. Therefore, it is essential to gain a comprehensive understanding of the molecular mechanisms driving MASLD and to develop targeted therapeutic interventions. Recent studies have underscored the critical role of posttranslational modifications (PTMs) of proteins in regulating MASLD. PTMs, such as ubiquitination, SUMOylation, Neddylation, and UFMylation, are known to modulate protein function and diverse cellular processes. Among these, ubiquitination is particularly noteworthy for its dual role in mediating protein degradation through the ubiquitin-proteasome system and in regulating cellular signaling pathways in a non-proteolytic manner, depending on the specific linkages formed at the seven distinct lysine residues (K6, K11, K27, K29, K33, K48, and K63) and the Met1-linked (M1) linear ubiquitin chain. Despite significant progress in this area, studies focusing on linkage-specific ubiquitination events that regulate MASLD remain relatively limited. Thus, this review aims to provide a comprehensive summary of the role of linkage-specific ubiquitination in regulating MASLD, as well as exploring other ubiquitinlike modifications that may contribute to its pathophysiology.